Effervescent deferiprone tablet

ABSTRACT

An oral pharmaceutical formulation for effervescent tablet of deferiprone is reported comprising of deferiprone and a taste-masking composition consisting of an effective amount of sweetener and flavoring agent and containing appropriate amount of alkali earth metal bicarbonate or carbonate and an organic carboxylic to afford a final acid pH of about 3.

FIELD OF THE INVENTION

This invention relates to a novel formulation of deferiprone for oraladministration

BACKGROUND

Oral administration of drugs is the most convenient and thereforepreferred method of transfer of medicine into the body. Injection, onthe other hand, is the least patient-compliant method. Accordingly,extensive research is carried out to formulate various drugs into orallybioavailable form. For example, cefuroxime axcetil was found to havelittle bioavailability in its crystalline from and it was administeredin injectable from to deliver the drug into the patient's blood stream(U.S. Pat. No. 5,847,118). Later on, however, it was discovered that itsamorphous form has oral bioavailability, possibly due a considerableincrease in the surface area of the amorphous powder, which upon contactwith the large amphiphilic surface area of the microvilli of the smallintestine becomes absorbed through a surface-surface phenomenon (J MedChem. 1998, 41, 5382-92.).

Beta thalassemia is hereditary blood disorder which is a result ofimbalanced beta-chain biosynthesis of hemoglobin. This results inreduced or absent beta chain, leading to early destruction of RBCs andanemia. To remedy the situation, patients with thalassemia major becometransfusion-dependent with subsequent iron overload. Excess iron resultsin the formation of reactive oxygen species (ROS) that causeirreversible damage to cells and organs of the patients. Accordingly,excess iron must be removed with iron chelators for the clinicalmanagement of thalassemia major (Karimian et al. Expert Opinion, Therap.Patents, 2011, 21, 819-856)

For many years, deferoxamine was the only clinically approved ironchelator available for the treatment of beta-thalassemia. Because of itshigh molecular weight, deferoxamine is not orally bioavailable and hasto be injected subcutaneously. Furthermore, due to its low half-life(t_(1/2)=5-10 minus), the drug has to be administered over a 12 hourperiod using a peristaltic pump. Combined, the mode and the extendedtime of administration results in a very low patient compliance.Accordingly, extensive research was carried out to discover a safe andeffective oral drug for the treatment of beta-thalassemia. Deferiprone,a bidentate iron chelator, was approved for clinical use as second linetherapy in 1999 in Europe and in 2012 in the US. 2011. The brand productis available as 500-mg film coated tablets.

In 2011, enteric-coated tablet, which was shown to eliminate thegastrointestinal side effects of Deferiprone, was introduced by AvicennaLaboratories Inc. (Iranian Patent 71,996). The contention of eliminationof gastrointestinal side effect by enteric coating the tables was basedon possible effect of concentration of the drug in the stomach of thepatients. The process of dissolution of the drug in the stomach maycreate an ever increasing concentration of the drug's activepharmaceutical ingredient in a small area of the stomach. The localconcentration of the chemical may then lead to nausea, the most commonlyobserved gastrointestinal side effect of deferiprone. This hypothesiswas tested in a single blind study of enteric-coated Deferiprone tableswith 100 thalassemia major patients, who refused to take the medicinebecause of its gastrointestinal effect-mainly nausea. It wassurprisingly discovered that 99 patients did not report anygastrointestinal side effects (Azarkeyvan A., Karimian K., MirtorabiMahabadi S., Narenjian A., Eslami M. Evaluation of gastric side effectsof new form of deferiprone, (L1; Enteric coated), 12^(th) InternationalConference on Thalassemia and Other Hemoglobinopathie, the 14^(th)Thalassemia International Foundation Conference Abstract 350, 11-15 May,2011, Anatalya, Turkey).

Exjade is the second clinically approved orally bioavailable ironchelator. This tridentate iron chelator was approved in the US andEurope in 2011 and was launched by Novartis. It is taken by patients asa suspension.

DETAILED DESCRIPTION

Deferiprone has been shown to be very effective in the removal of excessiron from the heart. This is particularly important because myocardialsiderosis, caused by excess iron in the heart, is the major cause ofdeath in beta-thalassemia patents.

Children show low compliance to oral administration of drugs in tabletor capsule form. This is especially true when the drug dose is large, asis the case with oral iron chelators. In fact, most oral medicine forchildren are formulated in form of suspension or syrups (e.g.erythromycin, . . . ). Due to its efficacy in the removal of excess ironfrom the heart, and to make the drug available for pediatric use, ApotexInc. formulated deferiprone in the form of syrup in 2009. Studies aimedat evaluation of deferiprone for pediatric use in children from 2 to 10years of age is funded by the EU and is being carried out in a number ofcenters in Europe and elsewhere (DEEP.com). Ferriprox syrup is availablein 200 ml bottles, 100 mg/ml. Dosing of the syrup in three equalportions per day using the appropriate dose of 75 mg/kg/day based theweight if the patient.

It became evident to us that formulation of deferiprone in aneffervescent form would have a number of important advantages over itsliquid form. First, it is well known that medicines are considerablymore stable in their solid rather than liquid form. Second, medicinesare much less likely to experience microbial growth in their solid formas compared to their liquid from since microbial growth require water,as in syrups or solutions (http://www.medscape.com/viewarticle/819276),and third, carrying a 200 ml bottle(https://www.medicines.org.uk/emc/medicine/21406) at all times by apatient is much more inconvenient that carrying a blister pack of 2tablets that can be converted to palatable liquid form by simpledissolution the tablet in a glass of water. In light of the above, wenow report a novel formulation of Deferiprone as effervescent tablet.

EXAMPLES

An oral effervescent pharmaceutical formulation comprising ofdeferiprone, a sweetener, a fruit flavor and an alkali earth metalbicarbonate or carbonate, an organic acid, a flavoring agent, a tastemasking agent, and lubricant having a final pH of 2.5 to 3.5 whendissolved in water

The following examples are not intended to limit the scope of thisapplication. These examples are provided in order to illustrate thebasic concept in this application. It is clear to men of art thatobvious variations to the examples provided below would not constitutenovelty.

Example 1. General Procedure for the production of Deferiproneeffervescent tablet. Deferiprone, Sodium Bicarbonate, Anhydrous CitricAcid, Sucrose, Sucralose, Orange Flavor, Colloidal Silicon Dioxide aremixed for 10 to 60 minutes and preferably for 30 minutes in a doublecone blender. Polyethylene glycol 6000 is added and blending iscontinued for 5-30 minutes, and preferably for 10 minutes. The mixtureis discharged and passed through a sieve (mesh 10) then pressed to formtablets and packaged in Alu-Alu blisters. The above procedure is carriedout under humidity-controlled environment.

Examples 1-9. The following ratios of the active ingredient andexcipients were used in various examples

Ingredients (mg/tablet) F₁ F₂ F₃ F₄ F₅ F₆ F₇ F₈ F₉ Deferiprone 500 500500 500 500 500 500 500 500 Sodium Bicarbonate 195 217 235 247 263 274288 300 307 Anhydrous Citric Acid 1750 1700 1700 1735 1675 1670 16301610 1600 Sucrose 400 400 400 400 400 400 400 400 400 Sucralose 130 130130 130 130 130 130 130 130 Orange Flavor 50 50 50 50 50 50 50 50 50Colloidal Silicon Dioxide 7 7 7 7 7 7 7 7 7 Polyethylene Glycol 6000 100100 100 100 100 100 100 100 100 Total Weight 3132 3104 3122 3169 31253131 3105 3097 3094

Disintegration times for the above examples are provided below:

F₁ F₂ F₃ F₄ F₅ F₆ F₇ F₈ F₉ Disintegration Time (min) 12 12 10 10 8 8 7 74

F₉ formulation was selected as the best formulation because of theirphysicochemical characteristics.

References

-   Palm, K. et al. Evaluation of dynamic polar molecular surface area    as predictor of drug absorption: comparison with other computational    and experimental predictors. J Med Chem. 1998, 41, 5382-92.-   Azarkeyvan A., Karimian K., Mirtorabi Mahabadi S., Narenjian A.,    Eslami M. Evaluation of gastric side effects of new form of    deferiprone, (L1; Enteric coated), 12^(th) International Conference    on Thalassemia and Other Hemoglobinopathie, the 14^(th) Thalassemia    International Foundation Conference Abstract 350, 11-15 May 2011,    Anatalya, Turkey.-   U.S. Pat. No. 5,847,118-   Karimian, K., et al. Advances in iron chelation: an update Expert    Opin. Ther. Patents, 2011, 21, 819, 856-   Tam, et al. Curr. Adv. Med. Chem. 2003, 10, 983-995.-   Rund, D., et al., New Eng. J. Med., 2005, 353, 1135-1146-   European Commission Decision of Nov. 19, 2007 (labeled “Not for    Publication”) approving Apotex's Ferriprox 100mg/ml oral solution,    available at    http://ec.europa.eu/health/documents/community-register/html/h108.htm    (Jul. 17, 2013).-   Hershko, C. et al. Ann. N.Y. Acad. Sci., 2005, 1054, 124-135.

We claim is:
 1. An effervescent, rapidly disintegrating oral dosage formof Deferiprone, which comprises of: (a) an active ingredient(Deferiprone), (b) an effervescent base, wherein said effervescent baseand consists essentially of (c) a pharmaceutically acceptable auxiliaryingredient. (i) at least one polysaccharide sweetener, (ii) an edibleorganic add, (iii) an alkali metal salt, carbonate or bicarbonate of thesaid edible organic acid citric
 2. The dosage form of claim 1, whereinthe dosage form comprises a tablet, granules, or sachets, said dosageform being adapted to be dissolved in water before being taken.
 3. Thedosage form of claim 1, wherein the dosage form comprises a buccal orsublingual tablet adapted to be administered directly into the oralcavity.
 4. The dosage form of claims 1, wherein said alkali-sensitiveactive ingredient is Deferiprone or a pharmaceutically acceptable saltthereof.
 5. The dosage form of claim 4, wherein said active ingredientis Deferiprone or its pharmaceutically effective salt.
 6. The dosageform of claim 1 wherein said effervescent base comprises a minimum ofabout 15% wt. sodium citrate.
 7. The dosage form of claim 1, whereinsaid effervescent base comprises a maximum of about 90% wt. of thedosage form.
 8. The dosage form of claim 1, said active ingredientcomprises from about 30% wt. to about 70% wt. of said effervescent base.9. The dosage form of claim 1 in which the flavoring agent selected fromthe group consisting of natural flavors, natural fruit flavors,artificial fruit flavors, peppermint, peppermint oil and mixturesthereof.
 10. The dosage form of claim 1 in which the flavoring agentcomprises of more than one agent.
 11. The dosage form of claim 1,wherein the dosage forms is an effervescent minitablet comprising fromabout 50 mg to about 1000 mg Deferiprone, and about 1200 mg of saideffervescent base.
 12. The dosage form of claim 1, wherein the dosageform is a buccal preparation comprising from about 50 to about 1000 mgDeferiprone and from about 100 to about 5000 mg of said effervescentbase.
 13. The dosage form of claim 13, wherein said buccal preparationcomprises from about 50 to about 1000 mg Deferiprone.
 14. The dosageform of claim 1, wherein said auxiliary ingredient comprises at leastone of (i) a colorant, and (ii) at least one sweetener.
 15. The dosageform of claim 15, wherein said sweetener is at least one of a sucrose,xylitol, D-glucose, sorbitol, mannitol, lactose, aspartame, sodiumsaccharine, acesulfam, and sodium cyclamate.
 16. A process for preparingthe dosage form of claim 1, which comprises separately granulating saidpolysaccharide and said organic edible acid, and adding saidalkali-sensitive active ingredient to the acidic granules, and ifnecessary drying the granules, and mixing the dried granules.
 17. Theprocess of claim 17, wherein said auxiliary ingredient is at least oneof lactose, sucrose, sorbitol, mannitol, starch, pectin, or cellulose.18. A process for preparing the dosage form of claim 1, which comprisesmixing all of the active ingredients and of said effervescent base,heating and drying the mixture.